MOLECULAR GENETIC EPIDEMIOLOGY STUDY OF ADHD/DRD4

ADHD/DRD4的分子遗传流行病学研究

• 批准号: 6392682
• 负责人: ROBERT K Moyzis
• 金额: $ 53.3万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-20 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6392682
• 关键词: alleles; attention deficit disorder; clinical research; clinical trials; data collection methodology /evaluation; disease /disorder etiology; dopamine receptor; family genetics; gene expression; genetic disorder; genetic polymorphism; genetic susceptibility; genotype; human genetic material tag; human subject; linkage disequilibriums; linkage mapping; nucleic acid sequence; polymerase chain reaction; receptor expression; restriction fragment length polymorphism; tyrosine 3 monooxygenase

Utilizing the vast number of marker loci being identified by the Human Genome Project, association studies are being applied to data on many complex disorders. Once an association is identified the issue for investigators is to determine what the association tells us about the disease process. When confirmed by numerous studies, the possibility of he association being a statistical artifact is remote. We are then left with two explanations: the associated allele plays a causative role in the disorder or the allele is in linkage disequilibrium with another locus(polymorphism) which does play a role. In order to truly understand the disorder we will have to distinguish between these, but how? This project is designed to capitalize on our ability to rapidly and accurately sequence DNA for a locus over a large number of individuals ascertained within a rigorous research design, and apply that information to determine the reason for he association. We have chosen to examine Attention Deficit Hyperactivity Disorder (ADHD) and the dopamine receptor gene DRD4. We first reported the association of ADHD with the D4.7 allele of this gene, which has now been confirmed by us and five other studies. ADHD affects about 3-5% of the school-aged population and is considered the most prevalent psychiatric disorder of childhood. Family, twin, and adoption studies have established a strong genetic basis for ADHD. Initial molecular genetic investigations of candidate genes focused on the neurotransmitter dopamine because most patients are responsive to methylphenidate. The DRD4 locus is a highly variable locus where the 7- repeat form of a 48 bp segment occurs in many allelic forms. Other polymorphisms have been identified in DRD4, some of which have known functional significance, but none of which have been evaluated in ADHD studies. Probands will be ascertained through clinical trials at the Child Development Center, UCI when they meet rigorous diagnostic criteria for ADHD. Probands, their parents, and siblings will be studied and their DNA sequenced for DRD4. Other dopamine pathway loci will be genotyped. Within those families who carry D4.7 we will determine the haplotype(s) present in affected individuals for all of the polymorphisms present in the DRD4 gene. For the non-D4.7 families we will test or tight linkage with the DRD4 region. If D4.7 is merely a marker in linkage disequilibrium with a causative polymorphism, then this latter subset of families should also show evidence for linkage.

利用人类基因组计划鉴定的大量标记位点，关联研究正在应用于许多复杂疾病的数据。一旦确定了关联，研究人员面临的问题就是确定该关联告诉我们有关疾病过程的哪些信息。当大量研究证实后，这种关联成为统计假象的可能性很小。然后我们有两种解释：相关的等位基因在疾病中起着致病作用，或者等位基因与另一个确实起作用的基因座（多态性）存在连锁不平衡。为了真正理解这种疾病，我们必须区分这些疾病，但是如何区分呢？该项目旨在利用我们对在严格的研究设计中确定的大量个体的基因座进行快速、准确的 DNA 测序的能力，并应用该信息来确定关联的原因。我们选择检查注意力缺陷多动障碍 (ADHD) 和多巴胺受体基因 DRD4。我们首先报道了 ADHD 与该基因的 D4.7 等位基因的关联，现已得到我们和其他五项研究的证实。 ADHD 影响约 3-5% 的学龄人口，被认为是儿童期最常见的精神疾病。家庭、双胞胎和收养研究为多动症奠定了坚实的遗传基础。候选基因的最初分子遗传学研究集中在神经递质多巴胺上，因为大多数患者对哌醋甲酯有反应。 DRD4 基因座是一个高度可变的基因座，其中 48 bp 片段的 7 重复形式出现在许多等位基因形式中。 DRD4 中还发现了其他多态性，其中一些具有已知的功能意义，但尚未在 ADHD 研究中进行评估。当先证者符合 ADHD 的严格诊断标准时，将通过 UCI 儿童发展中心的临床试验来确定。先证者、他们的父母和兄弟姐妹将接受研究，并对他们的 DRD4 进行 DNA 测序。其他多巴胺途径基因座将被基因分型。在那些携带 D4.7 的家族中，我们将确定受影响个体中存在的 DRD4 基因中存在的所有多态性的单倍型。对于非 D4.7 家族，我们将测试或与 DRD4 区域紧密连接。如果D4.7仅仅是具有致病性多态性的连锁不平衡的标记，那么后一个家族子集也应该显示连锁的证据。